Gause G E, Baker R, Cassin S
Department of Physiology, College of Medicine, University of Florida, Gainesville 32610.
Am J Physiol. 1988 Jan;254(1 Pt 2):H120-5. doi: 10.1152/ajpheart.1988.254.1.H120.
The effects of leukotriene D4 and the putative leukotriene receptor antagonist FPL 57231 were studied on the pulmonary circulation of alpha-chloralose-anesthetized fetal lambs close to term. At constant pulmonary inflow leukotriene D4 (LTD4, 0.1-10 micrograms), as bolus injections, caused dose-dependent increases in pulmonary vascular resistance. FPL 57231 (1.0-10 mg/kg) not only blocked the pressor responses to LTD4 but also lowered the normal pulmonary vascular resistance in a dose-dependent fashion. However, FPL 57231 also decreased the pulmonary pressor response to U 46619, a thromboxane A2 mimic, as well as the pressor response to phenylephrine HCl. Furthermore, the pressor responses to LTD4 were markedly reduced by cyclooxygenase inhibition. In preliminary experiments we demonstrated that the phenidone derivative, BW755C, which is a dual inhibitor of both cyclooxygenase and 5-lipoxygenase enzymes, did not block the pressor response to hypoxia. We conclude that FPL 57231 decreases fetal pulmonary vascular resistance by nonspecific mechanisms. Also the action of LTD4, is indirect and by way of the cyclooxygenase system. Although exogenous leukotrienes are able to produce a marked pulmonary pressor response, endogenous leukotrienes are probably not responsible for the hypoxic pulmonary pressor response of the fetal lung or its normally high pulmonary vascular resistance.
研究了白三烯D4和假定的白三烯受体拮抗剂FPL 57231对接近足月的α-氯醛糖麻醉的胎羊肺循环的影响。在肺血流量恒定的情况下，静脉推注白三烯D4（LTD4，0.1 - 10微克）可引起肺血管阻力呈剂量依赖性增加。FPL 57231（1.0 - 10毫克/千克）不仅可阻断对LTD4的升压反应，还能以剂量依赖性方式降低正常肺血管阻力。然而，FPL 57231也可降低对血栓素A2类似物U 46619的肺升压反应以及对盐酸去氧肾上腺素的升压反应。此外，环氧合酶抑制可显著降低对LTD4的升压反应。在初步实验中，我们证明了作为环氧合酶和5-脂氧合酶双重抑制剂的非那吡啶衍生物BW755C不会阻断对缺氧的升压反应。我们得出结论，FPL 57231通过非特异性机制降低胎羊肺血管阻力。LTD4的作用也是间接的，通过环氧合酶系统发挥作用。尽管外源性白三烯能够产生显著的肺升压反应，但内源性白三烯可能与胎羊肺的缺氧肺升压反应或其通常较高的肺血管阻力无关。
